Alzheimer's disease is a neurodegenerative disorder characterized by loss of memory and progressive declining of cognitive abilities. The disorder affects a significant proportion of the aging population. D. B. Carr et al., Current concepts in pathogenesis of Alzheimer's disease, 103(3A) AM. J. MED. 3S-10S (1997). Alzheimer's disease's common signs and symptoms include apathy, agitation, mood disturbances, irritability, disinhibition, delusions, aberrant motor behavior, and sleeping and eating abnormalities. Id.
There is much evidence indicating that the memory and attention deficits in patients with Alzheimer's disease are due to degeneration of cholinergic systems that originate in the basal-forebrain-cholinergic system and innervate the neocortex, hippocampus and other brain areas. Coyle et al., 219 SCIENCE 1184 (1983; R. Mayeux et al., Treatment of Alzheimer's disease, 341 N. ENGL. J. MED. 1670-1679 (1999).
The first class of drugs approved by the FDA for Alzheimer's treatment were cholinesterase inhibitors. Id. It has been postulated that reversible cholinesterase inhibitors act by selectively inhibiting acetylcholinesterase, the predominate cholinesterase in the brain, thereby increasing the concentration of acetyl choline and enhancing cholinergic function in the central nervous system. S. L. Rogers, et al., The pharmacology of a piperidine cholinesterase inhibitor, In, CHOLINERGIC BASIS FOR ALZHEIMER'S THERAPY 314-320 (Birkhauser ed. 1991); P. J. Tiseo et al., Metabolism and administration of 14C-donepezil in healthy volunteers: A single dose study, BRIT. J. CLINICAL PHARMACOL. (1998). Oral dosage forms of reversible cholinesterase inhibitors currently available include Aricept® (donepezil hydrochloride), Exelon® (rivastigmine tartrate), Reminyl® (galantamine hydrobromide) and the rarely prescribed Cognex® (tacrine hydrochloride). See e.g., E. L. Barner et al., Donepezil use in Alzheimer's disease, 32 ANN PHARMACOTHER., 70-77 (1998); R. Moretti, et al., Rivastigmine in subcortical vascular dementia: a comparison trial on efficacy an tolerability for 12 months follow-up, 8 EUR. J. NEUROL. 361-362 (2001); G. K. Wilcock, et al., Efficacy and safety of galantamine in patients with mild to moderate Alzheimer's disease; multicenter randomized controlled trial, 321 BMJ 1445-1491 (2000); D. Knopman et al., Long-term tacrin (Cognex) treatment: effects on nursing home placement and mortality, Tacrin Study Group, 47 NEUROLOGY 166-177 (1996).
Cortical neurodegeneration in some neuropathies (e.g., stroke, ischemia, etc.) has been attributed to glutamate binding to N-methyl-D-aspartate (“NMDA”) receptors, which play a crucial role in glutamate-induced neurodegeneration. Mattson et al., 13 BRAIN RES. 174 (1988); Choi et al., 23 J. NEUROSCI. RES. 116 (1989); Hartley et al., 250 J. PHARMACOL. EXP. THER. 752 (1989); Meldrum et al., 11 TRENDS PHARMACOL. SCI. 379 (1990).
Thus, in addition to the class of acetylcholinesterase inhibitors, Namenda® (memantine hydrochloride) is an oral, non-competitive antagonist of N-methyl-D-aspartate approved by the FDA for treatment of Alzheimer's. B. Reisberg et al., Memantine Study Group: Memantine in moderate-to-severe Alzheimer's disease, N. ENGL. MED. 1333-1341 (2003).
Current Alzheimer's treatments are only available in oral dosage form. PHYSICIAN'S DESK REFERENCE 1736, 1197, 2304 (Lori Murray, ed., 59th ed., 2005). A severe disadvantage inherent in such oral dosage forms is patient compliance. Alzheimer's patients often forget or refuse to ingest their medication. Thus, depending on the daily dosage requirements, the assistance of a caregiver may be required multiple times in a single day. For example, the Physicians' Desk Reference states that therapy with the orally administered donepezil should only be started if a caregiver is available to regularly monitor drug intake to avoid abrupt discontinuation of therapy. PHYSICIAN'S DESK REFERENCE 1197 (Lori Murray, ed., 59th ed., 2005).
Of the orally-administered Alzheimer's pharmaceuticals approved by the FDA, Donepezil hydrochloride tablet, or Aricept™, is one of the most prescribed. Donepezil binds to acetylcholinesterase via hydrogen bonding and is easily hydrolyzed by water, thus the duration of enzyme inhibition at the receptor level is very short, and referred to as reversible. Id.
Transdermal delivery systems that provide stable drug blood levels over an extended period (e.g., over a period of days) are advantageous over oral delivery forms because they improve patient compliance. For example, the patient does not have to remember to take the medication or carry pills for administration later in the day. This is particularly applicable to Alzheimer's patients.
But unfortunately, because of the skin's drug penetration resistance, only a limited number of drugs are bioavailable via transdermal administration. T. K. Ghosh, et al., Transdermal and Topical Delivery Systems: an Overview and Future Trends in, TRANSDERMAL AND TOPICAL DRUG DELIVERY SYSTEMS 8 (1997).
The skin is a complex multilayer organ with a total thickness of 2-3 mm. The panniculus adiposus, a variably thick fatty layer, is below the dermis. The dermis is a layer of dense connective tissue that supports the epidermis. The epidermis comprises a layer of epithelial cells and is about 100 μm thick. The epidermis is further classified into a number of layers, of which the outermost layer is the stratum corneum (15-20 μm thick). The stratum corneum comprises highly dense, keratinized tissue and is the skin's main source of penetration and permeation resistance. W. Montagna, et al., THE STRUCTURE AND FUNCTION OF SKIN (1974); K. A. Holbrook, K. A. et al., The Structure and Development of Skin, In, 1 DERMATOLOGY IN GENERAL MEDICINE, 97-145 (4th ed., Eds. T. B. Fitzpatrick et al., 1993).
Because of the skin's impermeability, in general, only approximately 1 mg of a drug is delivered across a 1 cm2 area of skin in 24 hours. T. K. Ghosh, et al., Transdermal and Topical Delivery Systems: an Overview and Future Trends in, TRANSDERMAL AND TOPICAL DRUG DELIVERY SYSTEMS 8 (1997). The higher the molecular weight, the less permeable the drug. Id. Considering the dosage requirements of various drugs, only less than one percent are anticipated to be candidates for transdermal delivery. Id.
What are needed are transdermal delivery systems that can overcome the skin's inherent permeation resistance to deliver Alzheimer's pharmaceuticals over an extended period at plasma concentrations comparable to the oral dosage forms.